1. Field of the Invention
The present invention relates to medical devices and techniques for rodent and small mammalian based research, in particular rodents with physiologic sensors such as pre-embedded research related hardware and external rodent pulse oximeter systems.
2. Background of the Invention
In conducting research on small mammals, such as, most commonly mice, a researcher must spend time and money on designing and implementing the data collection methods and devices that will be required. For example, Researchers have been embedding heart pumps and other hardware into cows and various other animals for years. Small mammals provide other unique problems for similar research. However it has been proposed for mice research to utilize embedded EEG electrodes and embedded electrode amplifiers with an embedded power supply all located within a mouse's skin. In this configuration an antenna protrudes from the mouse's head and EEG data is transmitted wirelessly from the antenna to a host computer for monitoring the mouse's brain activity.
There are several drawbacks with the existing procedures for performing research on small rodents. First, researchers must spend considerable time developing the tools to conduct their research instead of focusing on the specified research itself. This wasted set up time significantly delays the subsequent research, which is an impediment to the general progress of science and potentially very costly in competitive commercial areas.
Second, researchers will unduly waste materials in the development of the specialized tools. For example, in embedding hardware in small mammals, such as mice, the researcher's unfamiliarity with the devices and with the specific effect of anesthetic on the small mammals can lead to a very high morbidity rate. Loss rates as high as 33% for such procedures on mice would not be unexpected. Consequently, in this example, the researchers would have to spend time to design the desired embedded sensor configuration, develop a technique for applying the sensor and transmitter and power supply within the subject animals, purchase the equipment and animals in excess of what was needed due to loss rates, perform the operation for embedding the hardware in excess of what was needed due to loss rates, test the surviving embedded subjects to see which have the sensors working properly until enough validated test subjects are obtained to begin the study. There is a great need in the research area to reduce or eliminate such lead times, particularly in rodent based research such as mice based research.
There are certain companies that have attempted to address some of these concerns. Charles Rivers Labs acts as a service provider and offers a surgical process for implanting devices in small mammals, specifically rats, mice and guinea pigs. The various processes are performed by trained technicians, which can help reduce the loss rates. Specifically Charles Rivers Labs list the ability to provide blood pressure sensors, electrocardiograph sensors, electroencephalograph sensors, electromyography sensors, osmotic/infusion pump, vascular access port and small injectable devices in at least one of rats, mice or guinea pigs. Charles Rivers Labs will only operate on animals purchased from Charles Rivers Labs. Further, the devices to be implanted are the responsibility of the customer, who must select the appropriate sensor and advise Charles Rivers Labs of the sensor (and the desired sensor location). There is a very limited selection of device implantation processes that Charles Rivers Labs identifies for the customers, and of those listed only three (implantation of “osmotic/infusion pump”, “vascular access port” and “simple injectable device”) are available for mice. Charles Rivers Labs is willing to perform specialty operations. The services provided by Charles River Labs, and possibly other service providers, can reduce yield loss, but it does little to reduce lead time for research. The researcher must still identify and locate the desired sensor and sensor location on the mammal and then provide this material to a service provider, such as Charles Rivers Labs. Certain service providers, such as Charles Rivers Labs, limit the source of the animals further restricting the researcher.
The above stated problems are not limited to internal or embedded hardware devices for research in small mammals. Consider the problems associated with external physiologic sensors that are useful for research, such as oximeter and pulse monitoring technology, when applied to small mammals such as mice. These technologies are also of significant interest to researchers of small mammals as well, but the application of this technology to small mammals presents numerous difficulties. The inventor has identified that one of the most common difficulties with designing or implementing existing sensors for small mammal research is sensor sizing and placement in order to assure quality physiologic signals.
As background, one type of non-invasive physiologic sensor is a pulse monitor, also called a photoplethysmographs, which typically incorporates an incandescent lamp or light emitting diode (LED) to trans-illuminate an area of the subject, e.g. an appendage, that contains a sufficient amount of blood. FIG. 1 schematically illustrates the photoplethysmographic phenomenon. The light from the light source 10 disperses throughout the appendage, which is broken down in FIG. 1 into non-arterial blood components 12, non-pulsitile arterial blood 14 and pulsitile blood 16, and a light detector 18, such as a photodiode, is placed on the opposite side of the appendage to record the received light. Due to the absorption of light by the appendage's tissues and blood 12, 14 and 16, the intensity of light received by the photodiode 18 is less than the intensity of light transmitted by the LED 10. Of the light that is received, only a small portion (that effected by pulsitile arterial blood 16), usually only about two percent of the light received, behaves in a pulsitile fashion. The beating heart of the subject creates this pulsitile behavior. The “pulsitile portion light” is the signal of interest and is shown at 20, and effectively forms the photoplethysmograph. The absorption described above can be conceptualized as AC and DC components. The arterial vessels change in size with the beating of the heart. The change in arterial vessel size causes the path length of light to change from dmin to dmax. This change in path length produces the AC signal 20 on the photo-detector, IL to IH. The AC Signal 20 is, therefore, also known as the photo-plethysmograph.
The absorption of certain wavelengths of light is also related to oxygen saturation levels of the hemoglobin in the blood transfusing the illuminated tissue. In a similar manner to the pulse monitoring, the variation in the light absorption caused by the change in oxygen saturation of the blood allows for the sensors to provide a direct measurement of arterial oxygen saturation, and when used in this context the devices are known as oximeters. The use of such sensors for both pulse monitoring and oxygenation monitoring is known and in such typical uses the devices are often referred to as pulse oximeters. These devices are well known for use in humans and large mammals and are described in U.S. Pat. Nos. 4,621,643; 4,700,708 and 4,830,014 which are incorporated herein by reference.
With the above background, the researcher working with small mammals, in particular mice, is faced with several daunting questions when applying this technology to the desired subjects. The first question that people skilled in the art of human-based pulse oximeters ask is where do you put an oximeter sensor on a mouse? The problem is that a mouse's appendages and other hairless areas are smaller than the light emitters and light detectors employed in the external sensors. This causes light shunting on the appendages. Further, most manufacturers provide a light path to the photodiode, i.e. a window, that has larger dimensions than the photodiode itself. This may be done in order to make sure that that light that can enter the photodiode from the sides (up to an angle of 180 deg). This increases the shunting problems, particularly with small rodents.
Optical shunting in pulse oximeters is schematically shown in FIG. 2 and occurs when light from the emitter 10 reaches the detector 18 without passing through an appendage 24. Shunted light 26 is a portion of the total transmitted light that passes around the appendage 24 directly to the detector 18. Since shunted light 26 simply passes by the appendage 24, the appendage's tissue does not absorb it. If light shunting occurs, it creates an enormous amount of noise, or extraneous signal, in a photo-plethysmograph. When attempting photo-plethysmograph-based measurement on tiny subjects, such as rodents and in particular mice, light shunting is an enormous challenge. FIG. 3, illustrates the same emitter 10 and photodiodes 18 that have been utilized in the typical neonatal human sensors discussed above and applied the foot or paw 30 of a mouse. The emitter 10 and detector 18, illustrated in FIG. 3, are the same emitter and detector illustrated in FIG. 2, specifically a human infant pulse oximeter such as the type sold by NELLCOR under the trademark Oxisensor® II. As illustrated in FIG. 3, emitters 10 and detectors 18 utilized for humans will not work for mice and small rats because the fingers, toes and even the entire feet or paw 30 of these subjects are so small that significant optical shunting is unavoidable.
There is a further problem with other possible locations for the existing pulse oximeters sensors for small mammals such as mice. Unlike in humans, the remainder of a mouse's outer body, other than the hands and feet, is covered with hair. Hair attenuates the pulsitile light signal that is needed in order to calculate SpO2 (i.e. the blood oxygenation).
In addition to where to locate an appropriate pulse oximeter on a small rodent, there are other unique problems. If the rodent subject is not anesthetized, in a very short period of time, the rodent will destroy the sensor or sensor cable by biting it. Further, mice have extremely high heart rates (200 to 900 beats per minute). The existing sensors and associated software do not accommodate such rates. These extremes can be passed off as noise in existing oximeter sensors used on humans and large mammals, thereby effectively discarding the signal of interest. The inability to effectively use existing sensors on mice and small rodents have led certain companies to exclude their oximeters for use on small (or very small) mammals. For example, Kent Scientific sells a pulse oximeter for “use with small animals” and the device clearly states that “the available sensor will not work with mice”, which is particularly un-helpful for researchers utilizing mice.
It should be noted that an FFT-based measurement of respiratory rate using the same photoplethysmographic sensor that is utilized for pulse oximetry measurements has been tried/described by several researchers for humans and small mammals such as a dog or cat (see U.S. Pat. No. 5,396,893). Adult humans have respiratory rates in the range of 8 to 60 breaths/min. Adult humans have a heart rate in the range of 40 to 180 beats/min. Overall, the respiratory rate of humans is usually about ⅙ the heart rate. For example if a human is breathing at about 10 breaths per minute, the heart rate is usually somewhere around 60 beats per minute. Small mammals, such as mice and rats have a heart rate in the range of 200 to 900 beats/min. The respiratory rate of small mammals is also usually about ⅙ the heart rate. For a rat with a heart beat of 300 beats per minute, the respiratory rate is usually somewhere around 50 breaths per minute. The complex techniques for obtaining the respiratory rate from pulse oximetry sensors of the prior art simply do not translate to small mammals, such as mice.
There is a need in the industry to address the aforementioned drawbacks. There has also been a need to properly identify the drawbacks themselves as listed above, since once the failings of the prior art are properly identified the solutions thereto are more easily developed. There remains a need in the art to provide a simple, universal, cost effective system for providing medical devices for rodent based research applications. There remains a need in the art to provide a simple, cost effective, external mouse and small mammal pulse oximeter system for researchers. Various other objectives and advantages of the present invention become apparent to those skilled in the art as a more detailed presentation of the invention is set forth below.